Abstract

Question

In patients with a major affective disorder, is long-term lithium treatment associated
with lower suicide risk?

Data sources

Studies were identified by searching Current Contents, MEDLINE, PsycLIT, and PubMed from the 1960s. Pertinent publications (since 1949)
were also searched, and experts were contacted.

Study selection

Studies were selected if they examined lithium treatment in patients with bipolar
manic depressive disorder, major affective disorder (including recurrent major depression),
or schizoaffective disorder and included data for estimating suicide rates.

Data extraction

Data were extracted on patient diagnoses, study design, number of suicides, total
number of patients at risk for suicide, at-risk exposure times, and study quality.
Study quality was assessed by using a quality scoring scale (maximum score 7, which
referred to the highest-quality score) and expressed as a percentage of the maximum.

Commentary

The question of whether prophylactic lithium reduces the risk for suicide in mood
disorder is clinically important because of the high rate of suicide in mood disorder
and the lack of evidence that other treatments (such as antidepressants) affect suicide
rates. All research in suicide prevention faces the common challenges of the rarity
of suicide (even in high-risk groups) and the ethical constraints of clinical trials
on suicide. Good evidence on this question has been difficult to obtain.

The meta-analysis by Tondo and colleagues involves a careful search for all relevant
clinical trials. It concludes that patients with mood disorder who use lithium have
lower rates of suicide than those who do not use lithium. This finding concurs with
other recent reviews (1, 2).

The major limitation of this meta-analysis is that it is not confined to randomized
controlled trials. In fact, several of the included studies did not use parallel control
groups at all. This raises the issue of the comparability of patients who did and
did not take lithium. For example, some of the studies used control groups comprising
patients who had dropped out of lithium treatment. Such patients probably differ substantially
from patients who continued to take lithium; patients who were able to tolerate the
discipline of lithium treatment may have been at lower inherent risk for suicide than
those unable or unwilling to comply.

Thus, although the size of the antisuicidal effect found in the meta-analysis is striking,
to what extent the reduction in risk with lithium is a treatment effect rather than
a between-patient difference remains uncertain. If lithium does exert a true treatment
effect, the mechanism of action is unclear. It could be either a direct antisuicidal
effect or an effect secondary to prevention of relapse. Only the large-scale randomized
controlled trials in nonselected groups of patients that compare lithium with another
effective maintenance treatment and that use suicide (or a suitable proxy) as an outcome
measure will give a clearer answer to this question.